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Pleurisy can be categorized as primary or secondary, arising from immunological, tumorous, or microbial conditions. It often results in lung structure damage and the development of various respiratory issues. Among the different types, tuberculous pleurisy has emerged as a prominent focus for both clinical and scientific investigations. The IL-10 family, known for its anti-inflammatory properties in the human immune system, is increasingly being studied for its involvement in the pathogenesis of pleurisy. This review aims to present a detailed overview of the intricate role of IL-10 family members (specifically IL-10, IL-22, and IL-26) in human and animal pleuritic diseases or relevant animal models. These insights could serve as valuable guidance and references for further studies on pleurisy and potential therapeutic strategies.
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Interleucina-10 , Interleucina-22 , Interleucinas , Tuberculosis Pleural , Animales , Humanos , Interleucina-10/metabolismo , Interleucinas/metabolismo , Interleucinas/inmunología , Pleuresia/inmunología , Pleuresia/diagnóstico , Pleuresia/metabolismo , Tuberculosis Pleural/diagnóstico , Tuberculosis Pleural/inmunología , Tuberculosis Pleural/metabolismo , Tuberculosis Pleural/tratamiento farmacológicoRESUMEN
In this study, we propose a novel long short-term memory (LSTM) neural network model that leverages color features (HSV: hue, saturation, value) extracted from street images to estimate air quality with particulate matter (PM) in four typical European environments: urban, suburban, villages, and the harbor. To evaluate its performance, we utilize concentration data for eight parameters of ambient PM (PM1.0, PM2.5, and PM10, particle number concentration, lung-deposited surface area, equivalent mass concentrations of ultraviolet PM, black carbon, and brown carbon) collected from a mobile monitoring platform during the nonheating season in downtown Augsburg, Germany, along with synchronized street view images. Experimental comparisons were conducted between the LSTM model and other deep learning models (recurrent neural network and gated recurrent unit). The results clearly demonstrate a better performance of the LSTM model compared with other statistically based models. The LSTM-HSV model achieved impressive interpretability rates above 80%, for the eight PM metrics mentioned above, indicating the expected performance of the proposed model. Moreover, the successful application of the LSTM-HSV model in other seasons of Augsburg city and various environments (suburbs, villages, and harbor cities) demonstrates its satisfactory generalization capabilities in both temporal and spatial dimensions. The successful application of the LSTM-HSV model underscores its potential as a versatile tool for the estimation of air pollution after presampling of the studied area, with broad implications for urban planning and public health initiatives.
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Contaminantes Atmosféricos , Contaminación del Aire , Material Particulado/análisis , Contaminantes Atmosféricos/análisis , Monitoreo del Ambiente/métodos , Memoria a Corto Plazo , Contaminación del Aire/análisis , Redes Neurales de la Computación , CarbonoRESUMEN
Although many studies have discussed the impact of Europe's air quality, very limited research focused on the detailed phenomenology of ambient trace elements (TEs) in PM10 in urban atmosphere. This study compiled long-term (2013-2022) measurements of speciation of ambient urban PM10 from 55 sites of 7 countries (Switzerland, Spain, France, Greece, Italy, Portugal, UK), aiming to elucidate the phenomenology of 20 TEs in PM10 in urban Europe. The monitoring sites comprised urban background (UB, n = 26), traffic (TR, n = 10), industrial (IN, n = 5), suburban background (SUB, n = 7), and rural background (RB, n = 7) types. The sampling campaigns were conducted using standardized protocols to ensure data comparability. In each country, PM10 samples were collected over a fixed period using high-volume air samplers. The analysis encompassed the spatio-temporal distribution of TEs, and relationships between TEs at each site. Results indicated an annual average for the sum of 20 TEs of 90 ± 65 ng/m3, with TR and IN sites exhibiting the highest concentrations (130 ± 66 and 131 ± 80 ng/m3, respectively). Seasonal variability in TEs concentrations, influenced by emission sources and meteorology, revealed significant differences (p < 0.05) across all monitoring sites. Estimation of TE concentrations highlighted distinct ratios between non-carcinogenic and carcinogenic metals, with Zn (40 ± 49 ng/m3), Ti (21 ± 29 ng/m3), and Cu (23 ± 35 ng/m3) dominating non-carcinogenic TEs, while Cr (5 ± 7 ng/m3), and Ni (2 ± 6 ng/m3) were prominent among carcinogenic ones. Correlations between TEs across diverse locations and seasons varied, in agreement with differences in emission sources and meteorological conditions. This study provides valuable insights into TEs in pan-European urban atmosphere, contributing to a comprehensive dataset for future environmental protection policies.
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Contaminantes Atmosféricos , Ciudades , Monitoreo del Ambiente , Material Particulado , Oligoelementos , Material Particulado/análisis , Contaminantes Atmosféricos/análisis , Oligoelementos/análisis , Monitoreo del Ambiente/métodos , Europa (Continente) , Atmósfera/química , Estaciones del Año , Contaminación del Aire/análisisRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex respiratory condition influenced by environmental and genetic factors. Using next-generation sequencing, we aimed to identify dysregulated genes and potential therapeutic targets for COPD. METHODS: Peripheral blood leukocyte RNA profiles from COPD patients and healthy controls were analyzed using next-generation sequencing. Key genes involved in COPD pathogenesis were identified through protein-protein interaction network analysis. In vitro, bronchial epithelial cells treated with cigarette smoke extract (CSE) were used to study the effects on gene expression, cell viability, apoptosis, and ferroptosis. Additionally, Lipocalin 2 (LCN2) inhibition experiments were conducted to elucidate its role in COPD-related cellular processes. RESULTS: Analysis of RNA profiles revealed consistent downregulation of 17 genes and upregulation of 21 genes across all COPD groups. Among these, Cathelicidin Antimicrobial Peptide(CAMP), Defensin Alpha 4(DEFA4), Neutrophil Elastase(ELANE), LCN2 and Lactotransferrin(LTF) were identified as potentially important players in COPD pathogenesis. Particularly, LCN2 exhibited a close association with COPD and was found to be involved in cellular processes. In vitro experiments demonstrated that CSE treatment significantly increased LCN2 expression in bronchial epithelial cells in a concentration-dependent manner. Moreover, CSE-induced apoptosis and ferroptosis were observed, along with alterations in cell viability, Glutathione content, Fe2 + accumulation, ROS: Reactive Oxygen Species and Malondialdehyde levels, Lactate Dehydrogenase(LDH) release and Glutathione Peroxidase 4(GPX4) expression. Inhibition of LCN2 expression partially reversed these effects, indicating the pivotal role of LCN2 in COPD-related cellular processes. CONCLUSION: Our study identified six candidate genes: CAMP, DEFA4, ELANE, LCN2, and LTF were upregulated, HSPA1B was downregulated. Notably, LCN2 emerges as a significant biomarker in COPD pathogenesis, exerting its effects by promoting apoptosis and ferroptosis in bronchial epithelial cells.
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Apoptosis , Ferroptosis , Lipocalina 2 , Enfermedad Pulmonar Obstructiva Crónica , Análisis de Secuencia de ARN , Humanos , Ferroptosis/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Lipocalina 2/genética , Lipocalina 2/metabolismo , Apoptosis/genética , Masculino , Persona de Mediana Edad , Femenino , Anciano , Estudios de Casos y Controles , Células Epiteliales/metabolismo , Regulación hacia ArribaRESUMEN
Tungstates with a molecular formula A2W3O12 exhibits a wider negative thermal expansion (NTE) temperature range than molybdates but are challenging to synthesize, especially when A = Fe or Cr with metastable structures. To enhance the structural stability of Fe2W3O12, Sc with lower electronegativity is adopted to substitute Fe according to Fe2-xScxW3O12, considering the thermodynamic stability of Sc2W3O12. It is shown that the solid solutions can be easily synthesized and the phase transition temperature (PTT) can be tuned to well below room temperature (RT). Theoretical calculations and experimental results show that the formation energy decreases and the W-O bond in Fe-O-W gradually strengthens as the substitution of Sc in Fe2-xScxW3O12 increases, indicating an increase in structural stability. NTE is enhanced after phase transition with an increase in the Sc content. The reduction in PTT and the enhancement in NTE properties of Fe2W3O12 could result in a decrease in the effective electronegativity of the Fe-site elements, resulting in a low formation energy and strengthened W-O bond in Fe-O-W, which corresponds to a more stable structure.
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BACKGROUND: The effectiveness of cycloplegia in delaying the progression of myopia and its application in refractive examination in children have been extensively studied, but there are still few studies on the effects of atropine/tropicamide on ocular biological parameters. Therefore, the purpose of this study was to explore the effects of atropine/tropicamide on children's ocular biological parameters in different age groups and the differences between them. METHODS: This was a prospective observational study in which all school children were examined for dioptres and ocular biological parameters in the outpatient clinic, and 1% atropine or tropicamide was used for treatment. After examination, we enrolled the patients grouped by age (age from 2 to 12 years treated by atropine, 55 cases; age from 2 to 10 years treated by tropicamide, 70 cases; age from 14 to 17 years treated by tropicamide, 70 cases). The ocular biological parameters of each patient before and after cycloplegia were measured, and the difference and its absolute value were calculated for statistical analysis using an independent-samples t test. RESULTS: We compared the value and the absolute value of the differences in ocular biological parameters before and after cycloplegia in the same age group, and we found that the differences were not statistically significant (P > 0.05). There were significant differences in the corresponding values of AL, K1 and ACD among the different age groups (P < 0.05). Before cycloplegia, there were significant differences in AL, K, K1, K2 and ACD in different age groups (P < 0.05). However, the differences in AL, K, K1, K2 and ACD among different age groups disappeared after cycloplegia (P > 0.05). CONCLUSIONS: This study demonstrated that atropine/tropicamide have different effects on cycloplegia in children of different ages. The effects of atropine/tropicamide on ocular biological parameters should be fully considered when evaluating the refractive state before refractive surgery or mydriasis optometry for children of different ages.
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Presbiopía , Tropicamida , Humanos , Niño , Preescolar , Adolescente , Tropicamida/farmacología , Atropina/farmacología , Midriáticos/farmacología , Refracción Ocular , Cuerpo CiliarRESUMEN
BACKGROUND: The fracture risk of patients with chronic obstructive pulmonary disease (COPD) treated with inhaled corticosteroids is controversial. And some large-scale randomized controlled trials have not solved this problem. The purpose of our systematic review and meta-analysis including 44 RCTs is to reveal the effect of inhaled corticosteroids on the fracture risk of COPD patients. METHODS: Two reviewers independently retrieved randomized controlled trials of inhaled corticosteroids or combinations of inhaled corticosteroids in the treatment of COPD from PubMed, Embase, Medline, Cochrane Library, and Web of Science. The primary outcome was a fracture event. This study was registered at PROSPERO (CRD42022366778). RESULTS: Forty-four RCTs were performed in 87,594 patients. Inhaled therapy containing ICSs (RR, 1.19; 95%CI, 1.04-1.37; P = 0.010), especially ICS/LABA (RR, 1.30; 95%CI, 1.10-1.53; P = 0.002) and triple therapy (RR, 1.49; 95%CI, 1.03-2.17; P = 0.04) were significantly associated with the increased risk of fracture in COPD patients when compared with inhaled therapy without ICSs. Subgroup analyses showed that treatment duration ≥ 12 months (RR, 1.19; 95%CI, 1.04-1.38; P = 0.01), budesonide therapy (RR, 1.64; 95%CI., 1.07-2.51; P = 0.02), fluticasone furoate therapy (RR, 1.37; 95%CI, 1.05-1.78; P = 0.02), mean age of study participants ≥ 65 (RR, 1.27; 95%CI, 1.01-1.61; P = 0.04), and GOLD stage III(RR, 1.18; 95%CI, 1.00-1.38; P = 0.04) were significantly associated with an increased risk of fracture. In addition, budesonide ≥ 320 ug bid via MDI (RR, 1.75; 95%CI, 1.07-2.87; P = 0.03) was significantly associated with the increased risk of fracture. CONCLUSION: Inhalation therapy with ICSs, especially ICS/LABA or triple therapy, increased the risk of fracture in patients with COPD compared with inhaled therapy without ICS. Treatment duration, mean age of participants, GOLD stage, drug dosage form, and drug dose participated in this association. Moreover, different inhalation devices of the same drug also had differences in risk of fracture.
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Corticoesteroides , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Corticoesteroides/efectos adversos , Budesonida/efectos adversos , Duración de la Terapia , Nebulizadores y Vaporizadores , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológicoRESUMEN
The role of PM2.5 in the bronchial asthma remains unclear. In this study, the deficient mice of TLR4-/-, TLR2-/- and MyD88 -/- were used to establish asthma model. The effects of PM2.5 on the inflammatory response in lung tissue of these mice were observed. PM2.5 increased alveolar macrophages and neutrophils, up-regulated the IL-12 and KC expression in WT mice, but down-regulated their levels in TLR2 -/-, TLR4 -/- and MyD88 -/- mice. OVA+PM2.5 stimulated neutrophil count in WT mice, but it decreased in TLR2 -/- and TLR4 -/- mice. OVA+PM2.5 also increased the Eotaxin, IL-5, IL-13 and MCP-3 expression levels, and OVA specific IgE and IgG1 in serum also increased in WT group. PM2.5 may activate NF-κB through the TLR2/TLR4/MyD88 signaling pathway and aggravate allergic inflammation of lung in asthmatic mice. The microelements in PM2.5 granules, such as lipopolysaccharide, may be an important factor in the high incidence of asthma.
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Asma , FN-kappa B , Ratones , Animales , FN-kappa B/metabolismo , FN-kappa B/farmacología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/farmacología , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Asma/inducido químicamente , Transducción de Señal , Inflamación/inducido químicamente , Inflamación/metabolismo , Material Particulado/toxicidadRESUMEN
Hypoxic pulmonary hypertension (HPH) is characterized by elevated pulmonary artery resistance and vascular remodeling. Endoplasmic reticulum stress (ERS) is reported to be involved in HPH, but the underlying mechanisms remain uncertain. We found that Xbp1s, a potent transcription factor during ERS, was elevated in hypoxic-cultured rat PASMCs and lung tissues from HPH rats. Our in vitro experiments demonstrated that overexpressing Xbp1s can promote proliferation, cell viability, and migration and inhibit the apoptosis of PASMCs, while silencing Xbp1s led to the opposite. Through data-independent acquisition (DIA) mass spectrometry, we identified extensive proteomic alterations regulated by hypoxia and Xbp1s. Further validation revealed that p-JNK, rather than p-ERK or p-p38, was the downstream effector of Xbp1s. p-JNK inhibition reversed the biological effects of Xbp1s overexpression in vitro. In the animal HPH model, rats were randomly assigned to five groups: normoxia, hypoxia, hypoxia+AAV-CTL (control), hypoxia+AAV-Xbp1s (prevention), and hypoxia+AAV-Xbp1s (therapy). Adeno-associated virus (AAV) serotype 1-mediated Xbp1s knockdown in the prevention and therapy groups significantly reduced right ventricular systolic pressure, total pulmonary resistance, right ventricular hypertrophy, and the medial wall thickness of muscularized distal pulmonary arterioles; AAV-Xbp1s also decreased proliferating cell nuclear antigen expression and increased apoptosis in pulmonary arterioles. Collectively, our findings demonstrated that the Xbp1s-p-JNK pathway is important in hypoxic vascular remodeling and that targeting this pathway could be an effective strategy to prevent and alleviate HPH development.
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Hipertensión Pulmonar , Sistema de Señalización de MAP Quinasas , Proteína 1 de Unión a la X-Box , Animales , Proliferación Celular/genética , Modelos Animales de Enfermedad , Hipertensión Pulmonar/metabolismo , Hipoxia/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteómica , Arteria Pulmonar/metabolismo , Ratas , Ratas Sprague-Dawley , Remodelación Vascular , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a chronic progressive advanced disorder pathologically characterized by pulmonary vascular remodeling. Notch4 as a cell surface receptor is critical for vascular development. However, little is known about the role and mechanism of Notch4 in the development of hypoxic vascular remodeling. METHODS: Lung tissue samples were collected to detect the expression of Notch4 from patients with HPH and matched controls. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured in hypoxic and normoxic conditions. Real-time quantitative PCR and western blotting were used to examine the mRNA and protein levels of Notch4. HPASMCs were transfected with small interference RNA (siRNA) against Notch4 or Notch4 overexpression plasmid, respectively. Cell viability, cell proliferation, apoptosis, and migration were assessed using Cell Counting Kit-8, Edu, Annexin-V/PI, and Transwell assay. The interaction between Notch4 and ERK, JNK, P38 MAPK were analyzed by co-immunoprecipitation. Adeno-associated virus 1-mediated siRNA against Notch4 (AAV1-si-Notch4) was injected into the airways of hypoxic rats. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. RESULTS: In this study, we demonstrate that Notch4 is highly expressed in the media of pulmonary vascular and is upregulated in lung tissues from patients with HPH and HPH rats compared with control groups. In vitro, hypoxia induces the high expression of Delta-4 and Notch4 in HPASMCs. The increased expression of Notch4 promotes HPASMCs proliferation and migration and inhibits cells apoptosis via ERK, JNK, P38 signaling pathways. Furthermore, co-immunoprecipitation result elucidates the interaction between Notch4 and ERK/JNK/P38. In vivo, silencing Notch4 partly abolished the increase in RVSP and pulmonary vascular remodeling caused by hypoxia in HPH rats. CONCLUSIONS: These findings reveal an important role of the Notch4-ERK/JNK/P38 MAPK axis in hypoxic pulmonary remodeling and provide a potential therapeutic target for patients with HPH.
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Regulación de la Expresión Génica , Hipertensión Pulmonar/genética , Hipoxia/complicaciones , Miocitos del Músculo Liso/metabolismo , Receptor Notch4/genética , Remodelación Vascular/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Animales , Apoptosis , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipoxia/genética , Hipoxia/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Miocitos del Músculo Liso/patología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptor Notch4/biosíntesis , Transducción de Señal , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/biosíntesisRESUMEN
Tailoring the thermal expansion coefficient of negative thermal expansion (NTE) materials to achieve near-zero thermal expansion has attracted great attention recently. Here, LiFe diatoms are adopted to substitute Cu in Cu2P2O7 oxide to design Li-O-P and Fe-O-P linkages, with the stronger bond strength of Li-O and Fe-O compared to Cu-O and hence lowering the bond strength of P-O. With increasing the diatomic LiFe in (LiFe)0.5xCu2-xP2O7, new Raman bands corresponding to LiFeP2O7 appear and the NTE coefficient decreases gradually to near-zero thermal expansion at x = 1 (αv = -0.90 × 10-6 °C-1, -100 to 55 °C). Comparing (LiFe)0.5CuP2O7 with Cu2P2O7 and LiFeP2O7, the average bond length of P-O increases while the bond angle of P-O-P decreases, and this is verified by some weakened vibrational energies of terminal PO3 and P-O-P, resulting in the obvious red shift of Raman bands. Ceramic (LiFe)0.5CuP2O7 presents a lower difference in grain size and a higher relative density than Cu2P2O7 and LiFeP2O7.
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The extreme magnetoresistance (XMR) of some compounds, challenging our understanding of magnetoresistance, is an interesting topic in condensed-matter and materials physics and future device applications. Here, we reported magnetotransport and magnetic properties of the as-grown and post-annealed TaCo2Te2 single crystals. The resistivity evolution with temperature in the two TaCo2Te2 single crystals shows a metallic behavior. Below 50 K, the XMR effect for the two crystals is found, and MR values at 3 K under 9 T are about 3.72 × 103% for the as-grown TaCo2Te2 and 5.71 × 102% for the annealed samples, larger than that of the previous report. The studies on the Hall effect of the two TaCo2Te2 single crystals indicate the multiband feature with high carrier mobilities from a two-band model. Electron and hole concentrations and mobilities of as-grown samples are comparable, while for the annealed sample, the hole concentration and mobility are larger than the electron concentration and mobility. The carrier mobilities for the two TaCo2Te2 single crystals have the same order of magnitude, â¼103 cm2 V-1 s-1. The XMR effect may be from high carrier mobilities. Magnetization of the as-grown TaCo2Te2 decreases with increasing temperature, and a weaker magnetic transition at â¼150 K is observed. The annealed TaCo2Te2 shows no magnetic transition and just a paramagnetic behavior with rising temperature. These results indicate that defects/deficiencies may play an important role in magnetotransport and magnetic properties of the two TaCo2Te2 single crystals. These results are helpful in deeply understanding the XMR mechanism and magnetic properties in TaCo2Te2 and offer a way to study the magnetic properties of the XMR Co-Te system.
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Clarifying the relationship between urban expansion and ecosystem services (ESs) is critical for sustainable management of land resources and ecosystems. However, little is known about the relationship between the two at the cross-scale (particularly at the national-provincial scale). Therefore, we conducted a systematic assessment of the spatiotemporal dynamics and the relationship between urban expansion and ESs including food production (FP), soil conservation (SC), carbon sequestration (CS), and water yield (WY) in China from 1992 to 2020 on the national-provincial scale. The results show that China's urban expansion took up a large amount of cropland, accounting for 79.35% of the newly-added built-up land. Shandong had the largest expansion scale and the highest speed, Shanghai had the most pronounced expansion intensity, and more than 50% of the provinces were dominated by outlying expansion pattern. In terms of total change, the three ESs of FP, SC, and WY increased by 286.5 × 106 t, 1893.61 × 106 t, and 8337.20 × 106 mm, respectively, and CS decreased by 683.90 × 106 Mg C. However, in the urban expansion area, FP and CS net decreased by 1757.6 × 104 t and 19,640.19 × 104 Mg C, respectively, while SC and WY net increased by 347.52 × 104 t and 20,264.11 × 104 mm, respectively. Shandong contributed the most to changes in ESs in urban expansion areas. Urban expansion was significantly negatively correlated with FP and CS with the correlation coefficients > -0.8; it was significantly positively correlated with SC and WY, with coefficients of 0.714 and 0.413, respectively, and urban expansion had a lagged effect on ESs. The impact of urban expansion on ESs had a spatial spillover effect and showed prominent spatial clustering in Anhui, Henan, and Shandong. Based on these results, we proposed urban planning countermeasures grounded in the perspective of ES improvement, which would provide policy references for the sustainable management of the ecological environment and land resources.
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Conservación de los Recursos Naturales , Ecosistema , Secuestro de Carbono , China , SueloRESUMEN
We found previously that KLF4 expression was up-regulated in cultured rat and human pulmonary artery smooth muscle cells (PASMCs) exposed to cigarette smoke (CS) extract and in pulmonary artery from rats with pulmonary hypertension induced by CS. Here, we aim to investigate whether CS-induced pulmonary hypertension (PH) is prevented and ameliorated by targeted pulmonary vascular gene knockdown of KLF4 via adeno-associated virus 1 (AAV1)-KLF4-shRNA in vivo in rat model. The preventive and therapeutic effects were observed according to the different time-point of AAV1-KLF4-shRNA intratracheal administration. We tested haemodynamic measurements of systemic and pulmonary circulations and observed the degree of pulmonary vascular remodelling. In the preventive experiment, KLF4 expression and some pulmonary circulation hemodynamic measurements such as right ventricular systolic pressure (RVSP), mean right ventricular pressure (mRVP), peak RV pressure rate of rise (dP/dt max) and right ventricle (RV) contractility index were increased significantly in the CS-induced PH model. While in the prevention group (AAV1-KLF4-shRNA group), RVSP, mRVP, dP/dt max and RV contractility index which are associated with systolic function of right ventricle decreased and the degree of pulmonary vascular remodelling relieved. In the therapeutic experiment, we observed a similar trend. Our findings emphasize the feasibility of sustained pulmonary vascular KLF4 gene knockdown using intratracheal delivery of AAV1 in an animal model of cigarette smoke-induced PH and determined gene transfer of KLF4-shRNA could prevent and ameliorate the progression of PH.
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Dependovirus/metabolismo , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Factores de Transcripción de Tipo Kruppel/metabolismo , ARN Interferente Pequeño/uso terapéutico , Fumar/efectos adversos , Animales , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Diástole , Proteínas Fluorescentes Verdes/metabolismo , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/prevención & control , Factor 4 Similar a Kruppel , Masculino , Contracción Miocárdica , Osteopontina/metabolismo , Fosforilación , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Ratas Sprague-Dawley , Tráquea/patología , Tráquea/fisiopatologíaRESUMEN
Hypoxic pulmonary vascular remodeling is a pathological feature of pulmonary hypertension (PH). Our results showed that centromere-associated protein E (CENPE) expression in PH patients and hypoxia-induced PH rats was significantly higher than that in normal controls. In addition, CENPE deficiency significantly inhibited the development of pulmonary vascular remodeling and right ventricular hypertrophy. Moreover, knocking out CENPE effectively inhibited the proliferation and induced the apoptosis of primary pulmonary artery smooth muscle cells (PASMCs) in vivo. Furthermore, CENPE silencing by small interference significantly inhibited abnormal proliferation, apoptosis resistance, migration, and cell cycle arrest in hypoxia-induced PASMCs. Interestingly, we found that CENPE might exert its biological effect by targeting the transcription of CDK1 proteins.
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Proteína Quinasa CDC2/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/patología , Arteria Pulmonar/patología , Remodelación Vascular/fisiología , Animales , Proteína Quinasa CDC2/genética , Células Cultivadas , Proteínas Cromosómicas no Histona/genética , Modelos Animales de Enfermedad , Femenino , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/metabolismo , Hipoxia/genética , Hipoxia/metabolismo , Hipoxia/patología , Masculino , Persona de Mediana Edad , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Arteria Pulmonar/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
BACKGROUND: Hypoxic pulmonary hypertension (PH) is a refractory pulmonary vascular remodeling disease, and the efficiency of current PH treatment strategies is unsatisfactory. Tribbles homolog 3 (TRB3), a member of the pseudokinase family, is upregulated in diverse types of cellular stresses and functions as either a pro-proliferative or pro-apoptotic factor depending on the specific microenvironment. The regulatory mechanisms of TRB3 in hypoxic PH are poorly understood. METHODS: We performed studies using TRB3-specific silencing and overexpressing lentiviral vectors to investigate the potential roles of TRB3 on hypoxic pulmonary artery smooth muscle cells (PASMCs). Adeno-associated virus type 1(AVV1) vectors encoding short-hairpin RNAs against rat TRB3 were used to assess the role of TRB3 on hypoxic PH. TRB3 protein expression in PH patients was explored in clinical samples by western blot analysis. RESULTS: The results of whole-rat genome oligo microarrays showed that the expression of TRB3 and endoplasmic reticulum stress (ERS)-related genes was upregulated in hypoxic PASMCs. TRB3 protein expression was significantly upregulated by hypoxia and thapsigargin. In addition, 4-PBA and 4µ8C, both inhibitors of ERS, decreased the expression of TRB3. TRB3 knockdown promoted apoptosis and damaged the proliferative and migratory abilities of hypoxic PASMCs as well as inhibited activation of the MAPK signaling pathway. TRB3 overexpression stimulated the proliferation and migration of PASMCs but decreased the apoptosis of PASMCs, which was partly reversed by specific inhibitors of ERK, JNK and p38 MAPK. The Co-IP results revealed that TRB3 directly interacts with ERK, JNK, and p38 MAPK. Knockdown of TRB3 in rat lung tissue reduced the right ventricular systolic pressure and decreased pulmonary medial wall thickness in hypoxic PH model rats. Further, the expression of TRB3 in lung tissues was higher in patients with PH compared with those who have normal pulmonary artery pressure. CONCLUSIONS: TRB3 was upregulated in hypoxic PASMCs and was affected by ERS. TRB3 plays a key role in the pathogenesis of hypoxia-induced PH by binding and activating the ERK, JNK, and p38 MAPK pathways. Thus, TRB3 might be a promising target for the treatment of hypoxic PH.
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Estrés del Retículo Endoplásmico/genética , Regulación de la Expresión Génica , Hipertensión Pulmonar/genética , Hipoxia/complicaciones , Sistema de Señalización de MAP Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Remodelación Vascular/genética , Animales , Apoptosis , Comunicación Celular , Modelos Animales de Enfermedad , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipoxia/genética , Hipoxia/metabolismo , Masculino , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Regulación hacia ArribaRESUMEN
BACKGROUND: Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA. METHODS: Asthmatics (n = 115) and healthy controls (n = 28) underwent clinical assessment during 6-month follow-up with standardized therapy. Asthmatics were categorized by sputum differential cell count. The mRNA expressions were measured by RT-qPCR for sputum cytokines (IFN-γ, IL-1ß, IL-27, FOXP3, IL-17A, and IL-5). The protein of IL-1ß in sputum supernatant was detected by ELISA. Reticular basement membranes (RBM) were measured in the biopsy samples. The role and signaling pathways of IL-1ß mediating the epithelial-mesenchymal transition (EMT) process were explored through A549 cells. RESULTS: NA had increased baseline sputum cell IL-1ß expression compared to eosinophilic asthmatics (EA). After follow-up, NA had less improvement in FEV1 compared to EA. For all asthmatics, sputum IL-1ß mRNA was positively correlated with protein expression. Sputum IL-1ß mRNA and protein levels were negatively correlated to FEV1 improvement. After subgrouping, the correlation between IL-1ß mRNA and FEV1 improvement was significant in NA but not in EA. Thickness of RBM in asthmatics was greater than that of healthy controls and positively correlated with neutrophil percentage in bronchoalveolar lavage fluid. In vitro experiments, the process of IL-1ß augmenting TGF-ß1-induced EMT cannot be abrogated by glucocorticoid or montelukast sodium, but can be reversed by MAPK inhibitors. CONCLUSIONS: IL-1ß level in baseline sputum predicts the poor lung function improvement in NA. The potential mechanism may be related to IL-1ß augmenting TGF-ß1-induced steroid-resistant EMT through MAPK signaling pathways. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (IRB ID: 20150406).
Asunto(s)
Asma/inmunología , Transición Epitelial-Mesenquimal/inmunología , Interleucina-1beta/inmunología , Neutrófilos/inmunología , Mucosa Respiratoria/inmunología , Factor de Crecimiento Transformador beta/administración & dosificación , Células A549 , Adulto , Asma/genética , Asma/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Estudios de Seguimiento , Humanos , Interleucina-1beta/genética , Masculino , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Adulto JovenRESUMEN
Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling. Exploring new therapy target is urgent. The purpose of the present study is to investigate whether and how spliced x-box binding protein 1 (xbp1s), a key component of endoplasmic reticulum stress (ERS), contributes to the pathogenesis of PH. Forty male SD rats were randomly assigned to four groups: Control, Monocrotaline (MCT), MCT+AAV-CTL (control), and MCT+AAV-xbp1s. The xbp1s protein levels were found to be elevated in lung tissues of the MCT group. Intratracheal injection of adeno-associated virus serotype 1 carrying xbp1s shRNA (AAV-xbp1s) to knock down the expression of xbp1s effectively ameliorated the MCT-induced elevation of right ventricular systolic pressure (RVSP), total pulmonary resistance (TPR), right ventricular hypertrophy and medial wall thickness of muscularized distal pulmonary arterioles. The abnormally increased positive staining rates of proliferating cell nuclear antigen (PCNA) and Ki67 and decreased positive staining rates of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) in pulmonary arterioles were also reversed in the MCT+AAV-xbp1s group. For mechanistic exploration, bioinformatics prediction of the protein network was performed on the STRING database, and further verification was performed by qRT-PCR, Western blots and co-immunoprecipitation (Co-IP). DNA damage-inducible transcript 3 (Ddit3) was identified as a downstream protein that interacted with xbp1s. Overexpression of Ddit3 restored the decreased proliferation, migration and cell viability caused by silencing of xbp1s. The protein level of Ddit3 was also highly consistent with xbp1s in the animal model. Taken together, our study demonstrated that xbp1s-Ddit3 may be a potential target to interfere with vascular remodeling in PH.
Asunto(s)
Presión Arterial , Hipertensión Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Factor de Transcripción CHOP/metabolismo , Remodelación Vascular , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Apoptosis , Movimiento Celular , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/fisiopatología , Masculino , Monocrotalina , Músculo Liso Vascular/fisiopatología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Ratas Sprague-Dawley , Transducción de Señal , Factor de Transcripción CHOP/genética , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Derecha , Proteína 1 de Unión a la X-Box/genéticaRESUMEN
The study investigates the spatial pattern of black carbon (BC) at a high spatial resolution in Augsburg, Germany. Sixty two walks were performed to assess the concentrations of equivalent black carbon (eBC), ultraviolet particulate matter (UVPM), and equivalent brown carbon (eBrC) in different seasons and at different times of the day with a mobile platform (i.e., trolley). Along with BC measurements, images of street microenvironments were recorded. Meteorological parameters, including temperature, relative humidity, and wind speed, were monitored. The BC concentrations showed significant spatial heterogeneity and diurnal variations peaking in the morning and at night. The highest BC concentrations were observed near dense traffic. The correlations between BC and street views (buildings, roads, cars, and vegetation) were weak but highly significant. Moreover, meteorological factors also influenced the BC concentration. A model based on street view images and meteorological data was developed to examine the driving factors of the spatial variability of BC concentrations at a higher spatial resolution as different microenvironments based on traffic density. The best results were obtained for UVPM and eBC (71 and 70% explained variability). eBrC (53%), to which other sources besides road traffic can also make significant contributions, is modeled less well.
Asunto(s)
Contaminantes Atmosféricos , Emisiones de Vehículos , Contaminantes Atmosféricos/análisis , Carbono , Monitoreo del Ambiente , Alemania , Material Particulado/análisis , Hollín/análisis , Emisiones de Vehículos/análisisRESUMEN
BACKGROUND: In December 2019, the coronavirus disease 2019 (COVID-19) outbreak occurred in Wuhan. Data on the clinical characteristics and outcomes of patients with severe COVID-19 are limited. OBJECTIVE: We sought to evaluate the severity on admission, complications, treatment, and outcomes of patients with COVID-19. METHODS: Patients with COVID-19 admitted to Tongji Hospital from January 26, 2020, to February 5, 2020, were retrospectively enrolled and followed-up until March 3, 2020. Potential risk factors for severe COVID-19 were analyzed by a multivariable binary logistic model. Cox proportional hazard regression model was used for survival analysis in severe patients. RESULTS: We identified 269 (49.1%) of 548 patients as severe cases on admission. Older age, underlying hypertension, high cytokine levels (IL-2R, IL-6, IL-10, and TNF-α), and high lactate dehydrogenase level were significantly associated with severe COVID-19 on admission. The prevalence of asthma in patients with COVID-19 was 0.9%, markedly lower than that in the adult population of Wuhan. The estimated mortality was 1.1% in nonsevere patients and 32.5% in severe cases during the average 32 days of follow-up period. Survival analysis revealed that male sex, older age, leukocytosis, high lactate dehydrogenase level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19. CONCLUSIONS: Patients with older age, hypertension, and high lactate dehydrogenase level need careful observation and early intervention to prevent the potential development of severe COVID-19. Severe male patients with heart injury, hyperglycemia, and high-dose corticosteroid use may have a high risk of death.